As many as a third of persons with bipolar disorder (BD) are clinically unresponsive to treatment with mood stabilizers and thus suffer a devastating clinical course. Studies over decades, in search of molecular targets of mood stabilizers, have demonstrated that mood stabilizers, lithium in particular, robustly regulate various intracellular signaling mechanisms. It is still unknown, however, whether these drugs regulate intracellular signaling mechanisms in human neurons or if such regulation actually contributes to therapeutic efficacy. We propose to address these issues by testing the effects of lithium on neural tissues obtained from biopsies of the olfactory neuroepithelium (OE) of bipolar disorder (BD) patients. Several dimensions of biological processes may mediate intracellular signaling and complex behavioral manifestations such as therapeutic efficacy: signaling -> gene regulation -> cellular outputs -> neuronal functions -> mood states. To test therapeutic relevance of these biological processes, we will assess BD patients' OE biopsy tissues and relate intracellular signaling mechanisms, gene regulation and neuronal function to their clinical responsiveness to lithium treatment. To that end, we will recruit BD patients in a pair of clinical studies; one cross-sectional and one prospective. The cross sectional study (Aim 1a, Group I patients) will test molecular and cellular parameters in OE tissues as a molecular profile that influences the patient's response to lithium across their lifetime. The prospective study (Aim 1b, Group II patients) will test the relationships between signaling modulation and improvement of acute mood episodes. To accomplish the objectives of Aim 1, we will examine OE tissues of patients immediately after biopsy (ex vivo paradigm) to capture neuronal signaling at the time of procedure. To trace these signaling changes to their cellular outputs or neuronal modulation, we will examine gene transcription and upstream molecular events. Using an in vitro OE study paradigm, we will conduct a detailed analysis of upstream molecular events and downstream transcriptional regulation (Aim 2). To further connect these molecular events to cellular functions in the context of therapeutic efficacy, we will examine neurotrophic/protective effects in the OE tissues of Group I and Group II patients. In addition, we will test BDNF or NMDA receptor transmission as molecular mechanisms underlying neurotrophic/protective effects using in OE cultures (Aim 3). This project will, for the first time, attempt to connect the dots in the cascade of signaling -> neuronal functions -> treatment response using patients' neuronal cells and, as such, will address molecular and cellular pathways and specific mechanistic hypotheses regarding the neurobiological basis of treatment resistance in BD.